1-arylsulfonyl-3-(2-substituted ethyl) indoles



United States Patent 3,481,953 1-ARYLSULFONYL-3-(Z-SUBSTITUTED ETHYL)INDOLES David R. Herbst, Wayne, Pa., assignor to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware No Drawing.Original application Jan. 18, 1966, Ser. No. 521,431. Divided and thisapplication Dec. 18, 1967, Ser. No. 691,240

Int. Cl. C07d 27/56; A61k 27/00 US. Cl. 260-32612 25 Claims ABSTRACT OFTHE DISCLOSURE 1-arylsu1fonyl-3-(2 di(lower)alkylamino-, pyrrolidino-,piperidinoor morpholino-ethyl)indoles (A) are prepared by reacting thecorresponding 2-((di(lower)alkylamino-, pyrrolidino-, piperidinoormorpholino-ethyl)) indoles (B) with an arylsulfonyl halide in an inertsolvent in the presence of a strong base. Compounds (A) and theirnontoxic salts are therapeutically useful, demonstrating central nervoussystem depressant activity and anti-inflammatory activity.

This is a division of copending application Ser. No. 521,431, filed OnJan. 18, 1966, which in turn is a continuation-in-part of applicationSer. No. 383,971, filed on July 20, 1964, both now abandoned.

This invention relates to new and useful indole compounds as well as tothe novel method for their preparation. In particular, the presentinvention is concerned with 1-arylsulfonyl-3-(2-substituted ethyl)indoles having pharmacodynamic activity.

DESCRIPTION OF THE INVENTION The new compounds of this invention arerepresented by Formula A:

3-[2-(diethylamino)ethyl) 1 (p tolylsulfonyl)indole and itshydrochloride;

1-(p-methoxyphenylsulfonyl) 3 [2 (1 pyrrolidino) ethyl]indole and itshydrochloride.

3-(2-diethylaminoethyl) 1 (p methoxyphenylsulfonyl)indole and itshydrochloride;

3-[2-(1-pyrrolidino)ethyl] 1 (p tolylsulfonyl)indole and itshydrochloride;

1-(3,4-dichlorophenylsulfonyl) 3 [2 (1 pyrrolidino)ethyl]indole and itshydrochloride;

1-(3,4-dichlorophenylsulfonyl) 3 [2 (diethylamino) ethyl] indole and itshydrochloride;

3,481,953 Patented Dec. 2, 1969 l-(2,S-dichlorophenylsulfonyl) 3 [2 (1pyrrolidino)ethyl]indole and its hydrochloride; and

1-(2,S-dichlorophenylsulfonyl) 3 [2 (diethylamino) ethyl]indole and itshydrochloride.

When used herein and in the appended claims, the term (lower)alkylcontemplates hydrocarbon radicals, straight and branched chain,containing from about 1 to about 6 carbon atoms, illustrative of whichare methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl,3-methylpentyl, n-hexyl and the like. The term (lower)alkoxycontemplates hydrocarbonoxy radicals, straight and branched chain,containing from about 1 to about 6 carbon atoms, illustrative of whichare methoxy, ethoxy, npropoxy, i-propoxy, n-butoxy, t-butoxy, n-pentoxy,3-methylpentoxy, n-hexoxy and the like. The term halo includes chloro,bromo, iodo and fiuoro.

The new compounds of the present invention are prepared by firsttreating a solution of a selected indole of Formula B:

wherein R is as defined above, in an inert solvent such asdimethylformamide, toluene or the like with either an alkali metalhydride or an alkali metal amide at a temperature in the range of fromabout 25 C. to about C. for a period of from about 1 to about 5 hours.Thereafter, an arylsulfonyl halide, or an obvious chemical equivalentthereof, is added to the reaction mixture at a reaction temperature offrom about 25 C. to about 110 C. for a period of from about 12 to about18 hours, preferably about 16 hours. The reaction mixture then isextracted with either dilute aqueous hydrochloric acid or benzene toprovide a crude product which may be thereafter purified according toconventional procedures such as by chromatography.

The l-substituted bases obtained according to the foregoing reaction arethen convertible to their acid salts such as the hydrochloric acid saltsby treating an ethereal solution of the free base with either gaseous orisopropanolic hydrogen chloride. Other non-toxic,therapeutically-administrable acid-addition salts may also be preparedby treating the free base form of the compounds described with othersuitable organic or inorganic acids, Illustrative acids for this purposeinclude hydrobromic, sulfuric, phosphoric, nitric, benzoic,methylsulfonic, ptolylsulfonic, benzenesulfonic, naphthalenesulfonic,salicyclic, glycolic, acetic, maleic, succinic, tartaric, stearic,palmitic, citric, glutaric, lactic and the like.

The starting indoles generally identified by Formula B above are knownor prepared by methods such as that disclosed by M. E. Specter and W. C.Anthony, US. Patent 2,870,162 (Jan. 20, 1959) and T. Vitali and F.Mossini, Boll. Sci. Fac. Chim. Ind. Bologna, 17, 84-7 (1959) [C.A., 54,l9644b(1960)].

The new compounds of the present invention defined by Formula A aboveand their salts have valuable pharmacological properties. In particularthe new compounds of Formula A and their salts of the present inventionpossess central nervous system depressant activity and anti-inflammatoryactivity. These new compounds are therefore useful for treatingconditions in mammals responsive to administration of such agents.

When used for the purposes described above, it may be desirableaccording to conventional pharmaceutical practice to combine thespecific compound identified into compositions suitable for enteral orparenteral administration by combining the same with a pharmaceuticallyadministrable organic or inorganic carrier. The composition may beprepared in solid form, such as in tablets or in liquid form such as asolution, suspension or emulsion. Suitable liquid carriers includewater, gelatin, lactose, starch, talc, vegetable oils, alcohols,polyalcohols, gums, USP syrups and the like. The pharmaceuticalcompositions in addition to the active principle and the carrier mayinclude auxiliary materials such as coloring, stabilizing, wetting oremulsifying agents. It is of course recognized as essential that thecarrier as well as any other materials present with the active principlebe inert with respect thereto.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, teatment isinitiated with small dosages substantially less than the optimurn doseof the compound. Theeafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effiect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered'at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in the range of from about mg. to about 400 mg. per day,for a mammal of about 70 kg. average body weight, although as mentionedvariations will occur. However, a dosage level that is in the range offrom about 20 mg. to about 20 mg. per day is most desirably employed inorder to achieve effective results.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The specific examples whichfollow will provide a better understanding of the new compounds of thepresent invention as well as the method by which they are prepared. Theyare merely illustrative and are not to be construed to limit the scopeof the invention in any manner whatsoever. In these examples, thestarting indoles will, for convenience, be identified by numerals I-IV.The numerals represent the following compounds. (I) 3-[2- (1pyrrolidino)ethyl]indole; (II) 3 (2 diethylaminoethyl)indole; (III)3-(Z-piperidinoethyl)indole; and (IV) 3-(2-morpholinoethyl)indole.

Example 1.-1-phenylsulfonyl-3- [2-( 1-pyrrodidino)- ethyl]indole andhydrochloride A solution of 8.57 g. of 3-[2-(1-pyrrolidino ethyl]-indole(I) in 200 ml. of dry dimethylformamide (DMF) is stirred with 2.30 g. of50% sodium hydride/mineral oil dispersion for one hour, 8.45 g. ofbenzenesulfonyl chloride in 25 ml. of DMF is added dropwise and themixture is stirred at about 25 C. for 16 hours. Dissolution of thereaction mixture in benzene, washing of the organic solution with diluteaqueous potassium bicarbonate solution, and then with brine, anddistillation of the solvent gives an oily base. The oil is dissolved inabout 30 ml. of 1:1 benzene/n-hexane and is chromatographically purifiedon a column of 250 g. neutral, activity III alumina. The base (product)is eluted with 1:1 benzene/n-hexane and is dissolved in anhydrous etherand is treated with excess isopropanolic hydrogen chloride.Crystallization (twice) of the hydrochloric acid addition salt fromacetone provides the title product hydrochloride, M.P., (dec.) 193.5-l95C.,

4 Example 2.3- [2- diethylamino) ethyl] 1- (phenylsulfonyl)-indole andhydrochloride The procedure of Example 1 is repeated, substituting3-(2-diethylaminoethyl)indole (II) for 3-[2-(1-pyrrolidino)ethyl]-indole(I). The basic product is converted to the hydrochloride, which isrecrystallized from a mixture of acetone and isopropanol, M.P. (dec.),191193 C.,

3.95; 4.10; 7.33; 8.54 4; XZY F, 255 (6, 12,620); 280-94 (5, 4,250) aExample 3.1-(p-chlorophenylsulfonyl)-3-[2-(1-pyrrolidino)ethyl]indoleand hydrochlorine The procedure of Example 1 is repeated, substituting pchlorobenzenesulfonyl chloride for benzenesulfonyl chloride. The basicproduct is converted to the hydrochloride, which is recrystallized froma mixture of ethyl acetate and acetone, M.P. (dec.), 192-l94 C.,

Example4 z mon 254 14,960);

3 [2 (diethylamino)ethyl] 1 (p tolylsulfonyl) indole.'The hydrochlorideis recrystallized from acetone, M.P. (dec.), 183-186 C.,

A511, 3.95; 4.13; 7.37; 8.55 (6, 16,000); 279-293 (6, 6,700) mp 1 (pmethoxyphenylsulfonyl) 3 [2 (1 pyrrolidino)ethyl]-indole.--Thehydrochloride is recrystallized from acetone, M.P., 184-186 C.:

7135;, 3.93; 4.08; 7.34; 8.60; A231 250-257 (e, 19,860); 279-283 (6,6,880); 288-292(e, 5,710) m 3 (2 diethylaminoethyl) 1 (pmethoxyphenylsulfonyl)indole. The hydrochloride is recrystallized fromacetone, M.P. (dec.), 173.5-175.5 C.;

A531, 4.21; 7.33; 8.58;; M271 252-256 (6, 19,210); 281-285 (6, 6,140);289-294 (e, 5,150) m Example5.--3-[2-(l-pyrrolidino)ethyl]-1-(p-tolylsulfonyl)indole andhydrochloride A mixture of 8.01 g. of 3-[2-(1-pyrrolidino)ethyl]indole(I), ml. of dry DMF and 2.15 g. of 50% sodium hydride/mineral oildispersion is stirred 1 hour at about 25 C. and 8.53 g. ofp-toluenesulfonyl chloride is added slowly. The mixture is stirred forabout 16 hours at about 25 C. The crude product is extracted withbenzene and the extracts are washed with dilute aqueous bicarbonatesolution, dried and freed of solvent. The salt is generated byintroducing gaseous hydrogen chloride into the dry ether solution, ofthe base, M.P., -199 C. (softens 192 C.) after recrystallization fromacetone;

REEL, 3.93; 4.25; 7.39; 8.58 kfiffg 252.5 (6, 14,390) 279-293 (6, 4,950)

Example 6.-1-(3,4-dichlorophenylsulfonyl)-3- [2-(l-pyrrolidino)ethyl]indole and hydrochloride A mixture of 7.52 g. of3-[2-(1-pyrrolidino)ethyl]indole, 200 ml. of dry dimethylformamide (DMF)and 2.02 g. of 50% sodium hydride/mineral oil dispersion is stirred for0.75 hour, 10.72 g. of 3,4-dichlorobenzenesulfonyl chloride in 50 ml. ofDMF is added dropwise with cooling C.) and the mixture is stirred atabout 25 C. for 16 hours. Distillation of the solvent in vacuo,dissolution of the residue in benzene, washing of the organic phase withdilute, aqueous potassium bicarbonate then with brine and removal of thebenzene leaves the product. This is dissolved in a minimum of 1:1benzene: n-hexane is chromatographically purified on a 250 g. column ofneutral activity III alumina. Elution of the column with 1:1benzene-n-hexane provides the base which is dissolved in anhydrous etherand is treated with excess isopropanolic hydrogen chloride.Crystallization (twice) of the salt from acetone-ethyl acetate providesthe pure hydrochloride, M.P., 184-186 C.,

Example 7 The procedure of Example 6 is repeated withsuitablysubstituted starting materials and there are obtained:

1 (3,4 dichlorophenylsulfonyl) 3 [2 (diethylamino) ethyl]indole.--Thehydrochloride is recrystallized from acetone-ethyl acetate, M.P. (dec.),162-164 C.;

XKB:

1 (2,5 dichlorophenylsulfonyl) 3 [2 (diethylamino)ethyl]indole.Thehydrochloride is crystallized from methanol-ether, M.P. (dec),245.0247.5 C.;

153;, 3.97; 4.11; 7.24; 8.49; AEEZ 253-258 (6, 11,670); 279-292 (6,4,300) m Example8 The procedure of Examples 1, 5 and 6 are repeated withstoichiometrically-equivalent amounts of appropriately-substituted2-((di(lower)alkylamino-, pyrrolidino-, piperidinoand morpholino-ethyl))indoles and arylsulfonyl halides and the followingl-arylsulfonyl-3-(2-substituted ethyl) indoles are obtained:

These compounds are converted to their hydrochloric acid addition saltsby the procedures exemplified above.

The basic compounds of Examples 1-8 are dissolved in acetone and aretreated with stoichiometrically equivalent amounts of the followingacids in acetone and the solvent is removed by freeze-drying:hydrobromic, sulfuric, phosphoric, nitric, benzoic, methylsulfonic,p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic, salicyclic,glycolic, acetic, maleric, succinic, tartaric, stearic, palmitic,citric, glutaric and lactic. The corresponding acid addition salts areobtained as residues.

I claim:

1. A compound selected from the group consisting of a compound of theformula:

wherein R is di(lower)alkylamino, pyrrolidino, piperidino or morpholinoand R is phenylsulfonyl, halophenylsulfonyl, dihalophenylsulfonyl,(lower)alkoxyphenylsulfonyl or (lower)alkylphenylsulfonyl and thenon-toxic, therapeutically-administrable acid-addition salts thereof.

2. A compound as defined in claim 1 which is: l-phenylsulfonyl-3-[2-(1-pyrrolidino)ethyl]indole.

3. A compound as defined in claim 2 in the form of an acid addition saltwith hydrogen chloride.

4. A compound as defined in claim 1 which is: 3-[2- diethylamino ethyl]-1- (phenylsulfonyl) indole.

5. A compound as defined in claim 4 in the form of an acid addition saltwith hydrogen chloride.

6. A compound as defined in claim 1 which is: l-(pchlorophenylsulfonyl)-3- [2-( l-pyrrolidino)ethyl1indole.

7. A compound as defined in claim 6 in the form of an acid addition saltwith hydrogen chloride.

8. A compound as defined in claim 1 which is: l-(pchlorophenylsulfonyl-3 (Z-diethylaminoethyl indole 9. A compound as defined in claim 8 inthe form of an acid addition salt with hydrogen chloride.

10. A compound as defined in claim 1 which is: 3-[2- (diethylaminoethyl] -l- (p-tolylsulfonyl) indole.

11. A compound as defined in claim 10 in the form of an acid additionsalt with hydrogen chloride.

12. A compound as defined in claim 1 which is:l-(pmethoxyphenylsulfonyl) 3 [2-(1-pyrrolidino)ethyl]indole.

13. A compound as defined in claim 12 in the form of an acid additionsalt with hydrogen chloride.

14. A compound as defined in claim 1 which is: 3-(2- diethylaminoethyl)lp-methoxyphenylsulfonyl indole 15. A compound as defined in claim 14 inthe form of an acid addition salt with hydrogen chloride.

16. A compound as defined in claim 1 which is: 3-[2-l-pyrrolidino)ethyl] -1- (p-tolylsulfonyl) indole.

17. A compound as defined in claim 16 in the form of an acid additionsalt with hydrogen chloride.

. 18. A compound as defined in claim 1 which is: 1-(3,4-dichlorophenylsulfonyl) 3 [2-(1-pyrrolidino)ethyl]indole.

19. A compound as defined in claim 18 in the form of an acid additionsalt with hydrogen chloride.

7 20. A compound as defined in claim 1 which is: 1-(3,4-dichlorophenylsulfonyl) 3 [Z-(diethylamino)ethy11indole.

21. A compound as defined in claim 20 in the form of an acid additionsalt with hydrogen chloride.

22. A compound as defined in claim 1 which is: 1-(2,5- 5

dichlorophenylsulfonyl) 3 [2-(1-pyrrolidino)ethy1]indole.

23. A compound as defined in claim 22 in the form of an acid additionsalt with hydrogen chloride.

24. A compound as defined in claim 1 which is: 1-(2,5-dichlorophenylsul'fonyl) 3 [2-(diethylamino)ethyl]indole.

8 25. A compound as defined in claim 24 in the form of an acid additionsalt with hydrogen chloride.

References Cited UNITED STATES PATENTS 3,361,759 2/1968 Anthony et a1.260326.14

ALEX MAZEL, Primary Examiner 10 I A. NARCAVAGE, Assistant Examiner

